PROJECT SUMMARY/ABSTRACT Prostate cancer is the second leading cause of cancer associated deaths in men in the United States. The first line of treatment for men with advanced metastatic prostate cancer is hormone therapy. Although initial responses are observed, unfortunately, the disease commonly recurs in its aggressive hormone therapy- resistant form, which is largely responsible for prostate cancer-specific mortality. Thus, there is an urgent need to define the mechanisms that drive the aggressive disease. We have recently shown that UCHL1 protein is implicated in regulating aggressive prostate cancer growth and prostate cancer metastasis. We have strong preliminary evidence suggesting that UCHL1 may be a new promising therapeutic target for aggressive prostate cancer. We have recently demonstrated that inhibition of UCHL1 suppresses prostate cancer growth. The main goals of the proposed project are: 1) test the functional role of UCHL1 in advanced prostate cancer. 2) investigate the molecular mechanism through which UCHL1 signals in aggressive prostate cancer. 3) test the therapeutic potential of UCHL1 inhibition in animal models of aggressive disease and patient-derived xenografts in preclinical settings. Successful completion of the proposed research will lead to: 1) defining the role of UCHL1 in aggressive therapy- resistant prostate cancer, 2) the discovery of new molecular mechanisms underlying UCHL1 function and the development of aggressive prostate cancer which will guide us towards novel therapeutic strategies to target the advanced disease and 3) direct new strategies regarding novel therapeutic interventions to combat the deadly form of the disease.